Efficacy and safety of interim oncology treatments introduced for solid cancers during the COVID-19 pandemic in England: a retrospective evidence-based analysis

Summary Background The COVID-19 global pandemic placed unprecedented pressure on cancer services, requiring new interim Systemic Anti-Cancer Treatments (SACT) options to mitigate risks to patients and maintain cancer services. In this study we analyse interim COVID-19 SACT therapy options recommended in England, evaluating the evidence supporting inclusion and delineating how these have been integrated into routine cancer care. Methods We performed a retrospective analysis of interim Systemic Anti-Cancer Treatments endorsed by NHS England during the COVID-19 pandemic. Interim therapy options were compared to baseline (replacement) therapies by comparing data from the key pivotal trial(s) in terms of clinical efficacy and potential benefits (e.g., reduced immunosuppression or improved adverse effect profile) within the context of the pandemic. Furthermore, we evaluated the evolution of these interim SACT options, exploring if these have been integrated into current treatment pathways or are no longer accessible at the pandemic end. Findings 31 interim oncology treatment options, across 36 indications, for solid cancers were endorsed by NHS England between March 2020 and August 2021. Interim therapies focused on the metastatic setting (83%; 30/36), allowing greater utilisation of immune checkpoint inhibitors (45%; 14/31) and targeted therapies (26%; 8/31), in place of cytotoxic chemotherapy. Overall, 36% (13/36) of therapies could not have efficacy compared with baseline treatments due to a paucity of evidence. For those which could, 39% (9/23) had superior efficacy (e.g., overall survival), 26% (6/23) had equivocal efficacy and 35% (8/23) lower efficacy. 53% (19/36) of interim therapies had better or equivocal toxicity profiles (when assessable), and/or were associated with reduced immunosuppression. Almost half (47%; 17/36) of interim therapies did not have UK market authorisation, being classified as ‘off label’ use. Analysing access to interim options at the end of the pandemic (May 2023) identified 19 (53% 19/36) interim options were fully available, and a further four (11% 4/36) therapies were partially available. Interpretation Interim SACT options, introduced in England, across a range of solid cancers supported delivery of cancer services during the pandemic. Most interim therapies did not demonstrate superior efficacy, but provided other important benefits (e.g., reduced immunosuppression) in the context of the pandemic. Funding None.


Introduction
][7] The substantial reduction in UK oncology services during the COVID-19 pandemic, necessitated prioritisation of resources to areas deemed essential and/or offering highest patient benefit.][10] This facilitated cancer services prioritisation according to potential benefit, an approach replicated by many countries and international advisory bodies (e.g., European Society of Medical Oncology). 113][14][15] Early studies suggested a strong association between cytotoxic chemotherapy and severe COVID-19 sequelae, when compared to non-cytotoxic SACT (e.g., immune checkpoint inhibitors). 16,17However, it is now appreciated the urgency with which large retrospective cohort data was collected led to significant limitations (e.g., short followup, missing data), likely overestimated this risk significantly. 18,19Nevertheless, the oncology community needed to protect a population assumed highly vulnerable.Therefore, interim cancer treatment options were

Research in context
Evidence before this study Due to the rapid emergence of SARS-CoV-2 in 2020 there was a rapid decline in prescribing of Systemic Anti-Cancer Treatments in England, due primarily to concerns around immunosuppression.In England, new interim treatments were recommended by NHS England and NICE, in place of standard-of-care options, to facilitate cancer treatment during the pandemic based on recommendations of a Chemotherapy Clinical Reference Group.Previous evidence has demonstrated a high uptake of these interim therapy recommendations, reversing declines in anti-cancer prescribing at the start of the pandemic.However, the evidence supporting these recommendations (including many 'off label' uses) has not been published.Therefore, we searched PubMed for pivotal studies (search term in Appendix) for each interim therapy recommendation (Table 3), and baseline (replacement) therapy to identify the evidence supporting these.We identified comparative efficacy for 23 (64%; 23/36) interim COVID-19 treatment options However, for 13 (36%) interim COVID-19 treatment options no comparative efficacy could be identified.

Added value of this study
To our knowledge, this is the first study to assess the evidence base for interim therapy recommendations made by NHS England and NICE during the COVID-19 pandemic, transforming the management of many cancers during this challenging period.We identified 31 new interim Systemic Anti-Cancer Treatments (across 36 indications) endorsed by NHS England for the treatment of solid cancer(s) during the COVID-19 pandemic.Most interim therapy options advocated switching to less toxic and immunosuppressive therapies (e.g., cytotoxic chemotherapy to immune checkpoint inhibitors).Only 64% of interim therapy options had direct evidence supporting their use, in place of baseline treatments.35% of interim therapies involved switching to less efficacious options, and 47% were not licensed, requiring 'off-label' use, increasing prescriber responsibility.At the end of the pandemic only 53% of interim therapies remain fully available, with many being withdrawn from use.

Implications of all the available evidence
In England interim therapy options introduced by NHS England and NICE during the COVID-19 pandemic reversed declines in the prescribing of Systemic Anti-Cancer Treatments at the start of pandemic.However, only twothirds of these interim options had published evidence supporting their use in place of standard of care treatments.Our work highlights the need to put in place robust advisory and legislative frameworks to ensure the continuance and viability of cancer treatment in England in the face of any future global healthcare crisis.Clinical outcomes of patients receiving interim SACT therapies needs to be collected to inform about the viability, and success, of this strategy.Furthermore, this work has implications beyond the national level, and can be used as evidence to guide international stakeholders to allow for the global harmonisation of cancer management when faced with healthcare emergencies.
introduced by NHS England (Appendix), bypassing routine NHS and NICE processes (pre-pandemic) for new cancer drug approval, endorsing interim therapies, some of which were 'off label', to permit greater flexibility in cancer management during the pandemic, and ensuring clinicians had additional treatment options. 10,20nterim therapy options permitted alteration, or replacement, to the current SACT treatment recommendations, offering benefits in terms of resource delivery and/or COVID-19 related benefits (e.g., reduced immunosuppression).However, it remains unknown what evidence was used to support introduction of interim treatment options, and the value they added, especially in the context of the pandemic.
Interim treatment options were selected based on recommendations of the Chemotherapy Clinical Reference Group (CCRG), consisting of oncologists, specialist pharmacists, chemotherapy nurses and patient and public voice representatives, being endorsed by NHS England and NHS Improvement.Each interim treatment option was clinically assessed against five criteria (Table 2).For inclusion, a therapy must have met specification 4 (feasible to deliver) and 5 (adequate capacity to deliver), and at least one additional criterion from the following three specifications; reduced immunosuppressive (specification 1), administered at home or likely to result in less exposure to COVID-19 (specification 2) and/or be less resource intense (specification 3).It is unknown if interim therapies recommended, adhered to these, and/or focused on particular specifications.
In this study we sought to identify new oncology therapies approved for solid cancers, recommended during the COVID-19 pandemic by NHS England as interim treatment options (NICE guidelines [NG161]); (Appendix).We evaluated published evidence (e.g., pivotal trials); supporting interim therapy selection (comparing to baseline treatments), mapping clinical outcomes to the selection criteria (Table 2) and then categorising these based on treatment intent and risk-benefit ratio (Table 1).We evaluated the potential benefit these may offer in terms of severe adverse events, due to a higher probability of requiring medical intervention or hospital admission, and severe neutropenia, resulting in increased risk of sequelae from SARS-CoV-2 infection.Finally we established the availability of these interim therapy options at the end of the pandemic.

Methods
We evaluated new interim SACT therapy options endorsed for solid cancer by NHS England from the start of the COVID- Interim treatment options selected must meet criteria 1 or 2 or 3.In addition all treatments must meet both criteria 4 and 5 for selection.this list during the study period (December 2019-August 2022) where included in this analysis.This cohort study followed the STROBE reporting guidelines.This study was not submitted for institutional review board review because it used publicly available data and was not considered human subject research.

Data sources
We performed a retrospective analysis using data extracted from NICE guideline [NG161] COVID-19 rapid guideline: delivery of SACT. 10  All available data was extracted from COVID-19 interim treatment options to categorise therapy, tumour site, treatment setting (e.g., neoadjuvant, adjuvant, metastatic), specific indication, suggested replacement/baseline therapy option and rationale for inclusion if specified (e.g., reduced immunosuppression).Many interim options contained multiple indications (multi-faceted), for example nivolumab monotherapy in renal cell cancer could be used as firstor third-line therapy, and were therefore considered as separate options for analysis.For each therapy identified (including multi-faceted indications) the Electronic Medicines Compendium (EMC) website (https://www.medicines.org.uk/emc), which contains a database of all medicines licensed for use in the UK, and has been checked and approved by either the UK (e.g., MHRA) or European government agencies responsible, was evaluated to identify if this therapy held a valid UK market authorisation or was 'off-label' (date of censoring January 2024). 21Therapies were deemed to be fully licensed if the complete indication was specified on the EMC webpage.If only aspects of the interim indication were covered, then the drug was deemed to be partially covered.For example, atezolizumab in bladder cancer permitted first-line use across all patient types, however UK market authorisation specifies only use for patients considered cisplatin ineligible and tumours with PDL1 expression ≥5%, thus covering only part of the interim indication.If UK market authorisation did not apply to any part of the interim indication, then the use was considered 'off label'.The EMC webpage was analysed at the time of specification of new interim indications, and again at the date of censoring to ensure all changes were accounted for.
For interim COVID-19 therapy indications which held UK market authorisation, the pivotal trials used for regulatory approval were utilised for efficacy and safety analysis.If interim therapies were not licensed in the interim indication (e.g., 'off-label' use) other regulatory databases, such as the European Medicines Agency (EMA) or US Food and Drug Administration (FDA), were searched to identify appropriate clinical trials for analysis.If no appropriate studies could be identified then a PubMed search (see Appendix for Search terms and all trials used for analysis) was performed to identify other appropriate randomised controlled trials, metaanalysis, real world studies and cohort studies, to allow evaluation of comparative efficacy and/or safety.Finally for each interim therapy indication the NICE website and national Cancer Drugs Fund list (https:// www.england.nhs.uk/cancer/cdf/cancer-drugs-fund-list/) was cross-checked to identify if interim therapies had undergone formal approval (commissioning) by NHS England or remained available via the Cancer Drugs Fund.

Data analysis
Comparative clinical trials were analysed to identify appropriate clinical outcomes.In the metastatic setting, overall survival (OS) and, if not available surrogate endpoints progression free survival (PFS) and overall response rate (ORR) were selected, allowing assessment against COVID-19 prioritisation guidelines (Table 1), and for neoadjuvant and adjuvant options, pathological complete response (pCR) and disease-free survival (DFS) were used respectively.If these were not reported, or not comparable between the baseline therapy and new interim therapy, then clinical studies comparing toxicity were selected in a setting deemed closest to the original study to permit some analysis.For example, nivolumab was recommended as an interim therapy option for microsatellite instability-high upper gastrointestinal cancers (e.g., oesophageal) instead of chemotherapy, however, efficacy has not been directly compared, but safety information can be gleaned from the ATTRACTION-3 study.
Comparative efficacy was extracted by comparing clinical outcomes (e.g., ORR and OS) between the interim therapy and the treatment they replaced (baseline therapy).If these were compared directly in clinical trials (e.g., different treatment arms) these values were used.If there were no clinical trials directly comparing efficacy outcomes directly, then clinical benefit from equivocal studies (e.g., meta-analysis, retrospective cohorts), using the same clinical outcomes e.g., OS, PFS or ORR) were compared. 8A similar methodology was utilised to assess the safety profile using the National Cancer Institute Common Terminology Criteria for Adverse Events (v4.0).However, if there were no clinical trials directly comparing safety outcomes, then safety data from equivocal studies was evaluated.Incidences of grade 3 and 4 toxicity, and specifically neutropenia (significant risk factor for sequelae from SARS-CoV-2 infection) were compared between interim therapies and baseline treatment(s). 16This allowed interim therapies to be evaluated against COVID-19 Selection Criteria for Interim Treatment Options (Table 2).
NHS England interim COVID-19 SACT recommendations were withdrawn in August 2022, we therefore sought to evaluate which interim therapies remained available.All interim therapies were compared with current NICE guidelines to establish availability at the date of censoring.Therapy indications were deemed to be fully available if covered entirely by the NICE recommendation and partially if only aspects were covered.

Role of the funding source
No funding was obtained for this study.

Comparative toxicity and neutropenia
The comparative toxicity of interim treatment options compared to baseline options was assessable for 22 (61%; 22/36) therapies using 17 randomised controlled trials, directly comparing efficacy of interim options compared to baseline therapies, two retrospective cohort studies, one phase one trial and for two interim treatments, two different randomised controlled trials in the same setting where compared.Overall, 18 (81%; 18/22) interim therapies demonstrated a lower reported incidence of grade 3 and 4 toxicities and 1 (4%; 1/22) equivocal toxicity compared to baseline treatments.3 (14%; 3/22) interim therapies had a higher incidence of grade 3 and 4 toxicity.Comparable toxicities were not assessable for 12 (39%; 12/36) interim options due to no appropriate comparator study being identified.
Comparable incidences of significant neutropenia (grade 3 or 4) between interim therapies and baseline treatments were available for 17 (47%; 17/36) therapies using 15 randomised controlled trials, directly comparing efficacy of interim options compared to baseline therapies, one retrospective cohort study, one phase one trial and for two interim treatments, two different randomised controlled trials in the same setting were compared.16 (94%; 16/19) interim therapies offered a lower incidence of significant neutropenia compared to baseline treatments.Only 1 (6%; 1/17) interim therapy, temozolomide plus capecitabine in neuroendocrine cancer, showed an increased incidence of neutropenia compared to baseline therapy.Comparative neutropenia incidence was not assessable for 19 (53%; 19/36) interim therapies.
Analysing interim therapy options using COVID-19 selection criteria (Table 2), all treatments were deemed to meet specification 4 (feasible to deliver) and 5 (adequate capacity), being mandatory for inclusion as   1C).
Of the 25 therapies which specified an inclusion reason for inclusion (Appendix), we were able to verify 64% (16/25) interim therapies met the stated reason(s).For the remaining 9 (36%; 9/25) therapies no comparative study could be identified to validate inclusion reason and remain unvalidated.

Discussion
In this study we analysed the clinical evidence supporting interim SACT options during the COVID-19 pandemic, demonstrating that comparative evidence against replacement (baseline) treatments was only available for 64% (23/36) of interim therapies.For interim therapy (36%; 13/36) options where no comparator or no direct reference could be identified (e.g., PARP inhibitors, instead of chemotherapy, at first relapse for BRCA-positive PARP-naive patients ovarian cancer patients) it remains unknown what evidence, beyond the clinical opinion of the Chemotherapy Clinical Reference Group (CCRG), justified inclusion.Furthermore, it is also unknown if any CCRG members may have held any relevant conflicts of interest.47% (17/36) of interim therapies did not hold a full UK Market Authorisation meaning prescribing would be considered 'off label', placing greater responsibility upon the prescriber, this was reinforced by interim guidance stating, "responsibility for using these interim treatment regimens lies entirely with the prescribing clinician, who must discuss the risks and benefits of interim treatment regimens with individual patients, their families and carers" (Appendix). 22he paucity of data supporting these interim options would have represented a significant challenge for prescribers.As Interim treatment regimens were selected based on clinical opinion(s) from members of the CCRG, and being endorsed by NHS England and NHS Improvement, clearer communication of the rationale for inclusion, in terms of both efficacy and safety, and the proposed use, would have been extremely valuable to prescribers providing informed consent, and concordance of interim SACT options.Furthermore, as 35% of interim therapies involved switching to less efficacious options, the understanding, and quantification, in terms of other proposed benefits (e.g., reduced immunosuppression) related to the pandemic would have been important to communicate.This represents a missed opportunity to better inform prescribers of the rationale behind interim treatment selections.In terms of future pandemic planning, it is important to ensure clearer, and more robust, frameworks are in place to inform prescribers, and other healthcare professionals, of the evidence supporting these recommendations.
The COVID-19 rapid NICE guidelines for delivery of SACT were introduced to maximise cancer patient safety and facilitate the more rationale use of constrained NHS resources, throughout the pandemic.New SACT registrations fell sharply at the start of the pandemic, likely due to concerns around SACT safety (e.g., cytotoxic chemotherapy). 23However, following the introduction of COVID-19 interim treatment options new SACT registrations rebounded sharply, even surpassing pre-pandemic monthly levels, demonstrating a high, and accelerated, uptake of these new interim treatment options, especially for some drugs (e.g., enzalutamide in prostate cancer). 23Notably, a similar pattern was also seen in other UK countries (e.g., Scotland), who introduced their own equivalent SACT guidance. 24,25Further, it is perhaps unsurprising that half (16/36) of interim therapy options focused on three out of the four commonest cancers (lung, breast and colorectal) in the UK, likely associated with considerable resource-saving (e.g., chemotherapy chair time, pharmacy formulation time, monitoring requirements etc), but higher costs for the NHS.
For all interim therapy options, we were able to identify at least one COVID-19 selection criteria (in addition to mandatory criteria) to warrant inclusion in this guidance, with 44% (16/36) meeting ≥2 criteria concomitantly.However, assessing interim treatment options, based on treatment intent and risk-benefit ratio (Table 1) for treatment prioritisation demonstrated most therapies would achieve only a low priority (Priority 4-6) for clinical delivery, questioning the importance and true benefit these interim therapies offered.This is partly due to a smaller number (17%; 6/36) of non-metastatic (e.g., adjuvant, neoadjuvant) interim treatment options being included which typically receive higher priority ranking (Priority 1-4) compared to metastatic/non-curative treatment options (Priority 3-6), however it does reflect the uncertainty or lower efficacy of many metastatic treatment options.Furthermore, this is reflected in current NICE recommendations, with interim COVID-19 treatment options which received a higher priority (1-3) more likely to be available at the end of the pandemic compared to those which achieved a lower priority (4-6) ranking.Many low priority (4-6) ranked treatment options have been withdrawn, suggestive of little clinical value and/or unsustainable costs.
The administration of cytotoxic chemotherapy, and its concomitant immunosuppressive effects, was linked to deleterious outcomes in cancer patients who contracted SARS-CoV-2 in large UK retrospective studies, particularly those with baseline neutropenia. 26Therefore, it is unsurprising that the majority (52%) of interim therapy options advocated switching of cytotoxic chemotherapy to less immunosuppressive therapies (e.g., immune checkpoint inhibitors), potentially safeguarding cancer patients against serious sequelae from SARS-CoV-2 infection.Paradoxically, some interim treatment options had increased rates of neutropenia (e.g., temozolomide and capecitabine) or severe toxicities (e.g., sunitinib) compared to baseline options.However, in each case interim treatments offered other benefits (e.g., oral administration) (Table 2), potentially showing the balance given to each of the COVID-19 prioritisation criteria.Publication of the evidence supporting the recommendation of these interim options, would have enabled greater understanding of the benefits, and risks, of each treatment relative to the COVID-19 selection criteria governing inclusion.
The clinical outcomes of patients receiving these options remains unknown, reflecting a missed opportunity to understand interim therapy efficacy in a real-world setting, beyond eligibility criteria for clinical trials, and to inform about the viability of this strategy for future pandemic planning.Furthermore, as many patients may have had significant risk factors (e.g., >75 years or significant co-morbidities) for severe COVID-19 sequalae, it is unknown what consequence treatment (versus no treatment) may have had.Rigorous data collection, and rapid publication, of clinical outcomes in cancer patients was highly successful in informing treatment and vaccination decisions during the pandemic through rapid establishment of cooperative working groups (e.g., CCC19, OnCOVID, TERAVOLT). 4 similar approach could have proven successful in assessing, and modifying, interim therapy options, and should be considered in future pandemic planning.
Our work reflects the need for significant thinking around the advisory and legislative framework for national interim 'guidance' for cancer, and beyond, in the face of any future global healthcare crisis, acknowledging that implementing any new healthcare guidance, in cancer and beyond, during any healthcare emergency could be challenging.New frameworks need to be highly versatile and adaptive, allowing for rapid modifications when presented with new data, and involve additional stakeholders (e.g., MHRA) to allow for rapid modifications in drug labels based on recommendations.Future pandemic preparedness and resilience requires not just 'lessons learnt' from previous national experiences but also forward planning with an ability to adapt rapidly when presented with new data.
This study has several limitations which merit discussion.Firstly, some interim options could not be compared to baseline therapies due to a lack of appropriate comparative studies (e.g., PARP inhibitors instead of chemotherapy in frontline ovarian cancer).Therefore, these could not be compared meaningfully, however where possible relevant safety data (e.g., ARIEL-4) was analysed to provide insight.Secondly for some interim indications, clinical outcomes were not compared directly in clinical trials (e.g., different controlled arms), so had to be inferred from closely related studies.Thirdly, the scope of this study was focused on interim therapies for solid cancers, however several therapies were also approved for haematological malignancies.These were not included due to the scope of expertise of the author team but would provide further valuable insight.Fourthly, when primary OS data from pivotal trials was not available, alternative surrogate outcomes (e.g., PFS, ORR, pCR etc) as recognised by medicines agencies (e.g., the Food and Drug Administration) were used instead for comparison.Despite being useful, surrogate endpoints may not correlate well with clinical outcomes in some settings (e.g., pCR in early breast cancer). 27Finally, some interim baseline options (e.g., cisplatin and vinblastine in non-small cell lung cancer) are not listed in international guidelines (e.g., ESMO, NCCN) used for analysis and may represent an inaccuracy in the original listing, precluding further evaluation.

Conclusion
During the COVID-19 pandemic NHS England approved 31 interim therapies (across 36 indications) for solid cancers.The majority focused on greater use of immune checkpoint inhibitors and targeted treatments, in place of cytotoxic chemotherapy, conferring potential benefits in terms of reduced immunosuppression.For one-third of interim treatment options no objective clinical evidence could be identified to justify inclusion.Of those with evidence, 65% offered improved or equivocal clinical efficacy compared to baseline therapies, however around one-third of interim treatments had lower clinical benefit.Nearly all interim treatment options offered other benefits (e.g., reduced immunosuppression) in the context of the COVID-19 pandemic.Following the cessation of COVID-19 interim treatment guidelines and integration into routine care, only half of all treatment options remain fully available.

Fig. 1 :
Fig. 1: A: Categorisation of Systemic Anti-Cancer Therapies (SACT) based on treatment intent and risk-benefit ratio.Treatments were classified based on NHS COVID-19 prioritisation guidance [NG161] (Table 1).B: Number of therapies meeting each Selection Criteria for Interim Treatment Options During the COVID-19 Pandemic.*All therapies deemed to meet criteria 4 and 5 for inclusion.Treatments were classified based on NHS COVID-19 prioritisation guidance [NG161] (Table 2).C: Number of therapies meeting each selection criteria for inclusion as an interim treatment options.Treatments were classified based on NHS COVID-19 prioritisation guidance [NG161] (Table 2).D: UK Market Authorisation of Interim Treatment Options Approved During the COVID-19 Pandemic.E: Availability of Interim Treatment Options at the End of the COVID-19 Pandemic.

Table 1 :
19 pandemic (December 2019) until the withdrawal of interim COVID-19 therapy options (August 2022).Any therapy for solid cancer included on Curative therapy with a high (>50%) chance of success • Adjuvant or neoadjuvant treatment which adds at least 50% chance of cure to surgery or radiotherapy alone or treatment given at relapse Level 2 • Curative therapy with an intermediate (15-50%) chance of success • Adjuvant or neoadjuvant treatment which adds 20%-50% chance of cure to surgery or radiotherapy alone or treatment given at relapse Level 3 • Curative therapy with a low (10%-20%) chance of success • Adjuvant or neoadjuvant treatment which adds 10%-20% chance of cure to surgery or radiotherapy alone or treatment given at relapse • Non-curative treatment with a high (more than 50%) chance of more than 1 year extension to life Level 4 • Curative therapy with a very low (0%-10%) chance of success • Adjuvant or neoadjuvant treatment which adds less than 10% chance of cure to surgery or radiotherapy alone or treatment given at relapse • Non-curative treatment with an intermediate (15%-50%) chance of more than 1 year extension to life Level 5 • Non-curative therapy with a high (>50%) chance of palliation/temporary tumour control but <1 year expected life extension.Level 6 • Non-curative therapy with an intermediate (15-50%) chance of palliation or temporary tumour control and <1 year life extension Categorisation of Systemic Anti-Cancer Therapies (SACT) based on treatment intent and risk-benefit ratio (adapted from NICE guideline [NG161]).Specification Criteria 1 Treatment is less immunosuppressive and thereby mitigates a patient's likelihood of contracting COVID-19 or becoming seriously ill from COVID-19 Criteria 2 Treatment can be administered at home or in a setting that reduces the patient's exposure to COVID-19 Criteria 3 Treatment is less resource intensive and makes better use of clinical capacity Criteria 4 Treatment is feasible; that is, it is not likely to require significant service change or additional training Criteria 5 Likely to be adequate capacity in the relevant sector (such as home care providers) to deliver the treatment.
OS, Overall Survival; DFS, Disease Free Survival; pCR, Pathological Complete Response; PFS, Progression Free Survival; ORR, Overall Response Rate; DOR, Duration of Response; NR, Not Reported; N/A, Non-Assessable.Other Abbreviations: PDL1, Programmed death-ligand 1; HER2, Human epidermal growth factor receptor 2; CDF, Cancer Drug Fund; FOLFOX, Chemotherapy regimen made up of the drugs folinic acid, fluorouracil, and oxaliplatin; FOLFIRI, Chemotherapy regimen made up of the drugs folinic acid, fluorouracil, and irinotecan; MMR, Mismatch Repair; TPS, tumour proportion score; EGFR, Epidermal growth factor receptor.a All breast cancer types (e.g., Luminal A/B etc).b Results reflect all non-colorectal cancer and not specific to endometrial cancer.c Value reflects comparison in the TPS >1% group (Pembrolizumab versus Chemo-alone).d Platinum-based and Etoposide therapy (NCCN grade 1 classification).e Combination of BRAF/MEK (e.g., dabrafenib/trametinib deemed most appropriate (NCCN grade 1 classification)).f In Checkmate-067, the OS in the nivolumab/ipilimumab has not yet been reached but is estimated >60 months, so a value of 60-month has been used in this calculation.g ARIEL-4 selected for comparison (direct comparison of rucaparib versus chemotherapy in selected patient group (included both platinum sensitive and resistant groups)).h ENZAMET study used for toxicity (Anti-androgen + docetaxel compared to Aniandrogen + Enzalutamide arms compared; Selected toxicities (as reported) only).i Assumed instead of docetaxel (guidelines however not explicit about setting or replacement therapy).j ATTRACTION-3 study is a study of Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy and is not specific to MSI-H.k Pembrolizumab does hold a UK license for treatment of the following MSI-H (or dMMR) tumours in adults with unresectable or metastatic gastric, small intestine, or biliary cancer, who have disease progression on or following at least one prior therapy.l Direct comparison of chemotherapy versus Osimertinib used for toxicity analysis rather than comparative studies of tyrosine kinase inhibitors (e.g., FLAURA study) due to greater relevance.m Date of censoring is 1st January 2024.n Only Adverse Events with incidence >10% reported.o Similar mechanism of action to streptozocin.p All therapies deemed to meet criteria 4 & 5 for inclusion (not therefore assessed).